Regulation of metabolism by miR-378

The present invention provides a method of regulating fatty acid metabolism in a cell by contacting the cell with a modulator of miR-378 and/or miR-378* activity or expression. The present invention also provides a method of treating or preventing a metabolic disorder, such as obesity, diabetes, or metabolic syndrome, in a subject by administering to the subject an inhibitor of miR-378 and/or miR-378* expression or activity. Methods of treating or preventing pathologic cardiac hypertrophy, cardiac remodeling, myocardial infarction, or heart failure in a subject by inhibiting the expression or activity of miR-378 and/or miR-378* in a subject are also disclosed.Board of Regents, University of Texas Syste

Micro-RNAS that control myosin expression and myofiber identity

The present invention relates to the identification of two microRNAs, miR-499 and miR-208b, that repress fast skeletal muscle contractile protein genes. Expression of miR-499 and/or miR-208b can be used to repress fast fiber genes and activate slow fiber genes in the treatment of musculoskeletal disorders. Inhibition of miR-499 and/or miR-208b is proposed as a treatment for cardiac hypertrophy, myocardial infarction, and/or heart failure. Pharmaceutical compositions comprising antagonists and agonists of miR-499 and miR-208b function are also disclosed.Board of Regents, University of Texas Syste

Micro-RNAs of the miR-15 family modulate cardiomyocyte survival and cardiac repair

A family of microRNAs, called the miR-15 family, which includes miR-195, are shown to be up-regulated during pathological cardiac remodeling and repress the expression of mRNAs required for cell proliferation and survival, with consequent loss of cardiomyocytes. Strategies to block expression of the miR-15 family in the heart as a treatment for diverse cardiac disease are provided.Board of Regents, University of Texas Syste

Micro-RNA family that modulates fibrosis and uses thereof

The present invention relates to the identification of a microRNA family, designated miR-29a-c, that is a key regulator of fibrosis in cardiac tissue. The inventors show that members of the miR-29 family are down-regulated in the heart tissue in response to stress, and are up-regulated in heart tissue of mice that are resistant to both stress and fibrosis. Also provided are methods of modulating expression and activity of the miR-29 family of miRNAs as a treatment for fibrotic disease, including cardiac hypertrophy, skeletal muscle fibrosis other fibrosis related diseases and collagen loss-related disease.Board of Regents, University of Texas Syste

Inhibition of histone deacetylase as a treatment for cardiac hypertrophy

The present invention provides for methods of treating and preventing cardiac hypertrophy. Class II HDACs, which are known to participate in regulation of chromatin structure and gene expression, have been shown to have beneficial effects on cardiac hypertrophy. Surprisingly, the present invention demonstrates that HDAC inhibitors inhibit cardiac hypertrophy by inhibiting fetal cardiac gene expression and interfering with sarcomeric organization.Board of Regents, University of Texas Syste

A neonatal blueprint for cardiac regeneration

Adult mammals undergo minimal regeneration following cardiac injury, which severely compromises cardiac function and contributes to the ongoing burden of heart failure. In contrast, the mammalian heart retains a transient capacity for cardiac regeneration during fetal and early neonatal life. Recent studies have established the importance of several evolutionarily conserved mechanisms for heart regeneration in lower vertebrates and neonatal mammals including induction of cardiomyocyte proliferation, epicardial cell activation, angiogenesis, extracellular matrix deposition and immune cell infiltration. In this review, we provide an up-to-date account of the molecular and cellular basis for cardiac regeneration in lower vertebrates and neonatal mammals. The historical context for these recent findings and their ramifications for the future development of cardiac regenerative therapies are also discussed

Twist Is Required for Muscle Template Splitting during AdultDrosophilaMyogenesis

AbstractThe basic helix–loop–helix transcription factor Twist is required for normal development of larval and adult somatic muscles inDrosophila.Adult flies normally have six pairs of dorsal longitudinal indirect flight muscles (DLMs), whereas when Twist function is reduced, only three pairs of DLMs are formed. Althoughtwistis expressed in precursors of adult muscles throughout the larval and early pupal stages, we demonstrate that Twist function is required only during the late larval stage for DLM patterning. In wild-type flies, this is just prior to the time when three pairs of persistent larval muscle fibers split longitudinally to form templates for the six pairs of DLMs. By examining sections at various times during pupal development, we found that splitting of the larval muscles does not occur intwistmutants, indicating that Twist function is required to induce major changes in the larval templates prior to differentiation. The function of Twist in larval muscle splitting is likely mediated by myocyte enhancer factor-2 (MEF2) since inMef2hypomorphic mutants splitting is also reduced andMef2expression is dependent upon Twist. Our findings define specific roles for Twist and MEF2 during pupal myogenesis and demonstrate that these transcription factors function in adult muscle precursor cells to regulate downstream factors controlling muscle cell splitting and morphogenesis

DifferentMRF4Knockout Alleles Differentially Disrupt Myf-5 Expression:cis-Regulatory Interactions at theMRF4/Myf-5Locus

AbstractThree different null alleles of the myogenic bHLH geneMRF4/herculin/Myf-6were created recently. The three alleles were similar in design but were surprisingly different in the intensity of their phenotypes, which ranged from complete viability of homozygotes to complete lethality. One possible explanation for these differences is that each mutation altered expression from the nearbyMyf-5gene to a different extent. This possibility was first raised by the observation that the most severeMRF4knockout allele expresses no Myf-5 RNA and is a developmental phenocopy of theMyf-5null mutation. Furthermore, initial studies of the two weaker alleles had shown that their differences in viability correlate with the intensity of rib skeletal defects, and the most extreme version of this rib defect is the hallmark phenotype ofMyf-5null animals. In the present study we tested this hypothesis for the two milderMRF4alleles. By analyzing compound heterozygous animals carrying either the intermediate or the weakestMRF4knockout allele on one chromosome 10 and aMyf-5knockout allele on the other chromosome, we found that both of theseMRF4alleles apparently downregulate Myf-5 expression by acis-acting mechanism. Compound heterozygotes showed increased mortality of the normally viableMRF4allele, together with intensified rib defects for bothMRF4alleles and increased deficits in myotomal Myf-5 expression. The allele-specific gradation in phenotypes also suggested that rib morphogenesis is profoundly sensitive to quantitative differences in Myf-5 function if Myf-5 products drop below hemizygous levels. The mechanistic basis forcisinteractions at theMRF4/Myf-5locus was further examined by fusing a DNA segment containing the entireMRF4structural gene, including all sequences deleted in the threeMRFknockout alleles, with a basal promoter and alacZreporter. Transgenic embryos showed specific LacZ expression in myotomes in a pattern that closely resembles the expression of Myf-5 RNA.cis-acting interactions betweenMyf-5andMRF4may therefore play a significant role in regulating expression of these genes in the early myotomes of wildtype embryos